PROJECT 1: SUMMARY/ABSTRACT The concept of the exposome involves not only the combined effects of multiple chemicals, it entails the social and lifestyle factors that influence chemical toxicity, and the idea that the specific life stage of exposure can affect disease risks. Millions of people in the US are exposed to arsenic, which is ranked first on the Superfund chemical priority list. For several reasons, northern Chile is one of the best places in the world to study arsenic. First, this is the driest habitable place on earth, and despite its large population, it has very few individual water sources, with essentially each city being supplied by its own single municipal source. Second, these sources have had a wide range of arsenic concentrations, and arsenic records on all of these sources are available for over 50 years. Because of this, one simply needs to know what cities a person has lived in during which years to have a good idea of that person's lifetime arsenic exposure. This type of lifelong exposure data is not available in any other area in the world including the US. Third, the largest city in the area, Antofagasta, had a distinct period of high exposure beginning in 1958 when two rivers with high arsenic concentrations were diverted to the city for drinking, and ending in 1970 when an arsenic treatment plant was installed. Studying health effects now in people who were born during this distinct exposure period offers a rare opportunity to examine the impacts of early-life exposure on adult disease. Superfund has been supporting research in this area for 20+ years, and we have made a large number of novel discoveries. We found that early-life arsenic exposure was associated with >5-fold significant increases in adult lung cancer, >7-fold increases in bladder cancer, and respiratory effects similar to those seen with heavy smoking. We also identified marked increases in susceptibility due to arsenic metabolism, genetics, and common co-exposures like second-hand smoke and workplace exposures. Most recently, we found that arsenic-related cancer and lung disease were much greater in people who were overweight (e.g. synergy index=4.05, 95%CI=1.27?12.88). Here, we propose to use the unique exposure scenario in Chile to explore associations between arsenic and hypertension and endocrine diseases like prostate cancer and diabetes. Currently, data linking these outcomes to arsenic are mixed or controversial. However to date, no study has examined them using information on lifetime exposure, and no study has examined the potential modifying effects of early-life exposure, obesity, or stress. This is important since our recent research suggests that each of these factors may play a major role in arsenic-related disease. Overall, the significance of our project lies in the facts that arsenic exposure in the US is widespread, and that diabetes, hypertension, and prostate cancer are major causes of morbidity and mortality here. It is also lies in the facts that obesity and stress are common and important risk factors for disease, and that little is currently known about the long-term effects of early-life exposure. Our goal is to provide new information on these issues that could have important implications for US policies on arsenic and other chemical exposures.